The present study was designed to investigate the antihypertensive effect of Melothria maderaspatana leaf fractions on deoxycorticosterone acetate (DOCA)-salt-induced hypertensive rats and to identify compounds from the active fraction by GC-MS analysis. Administration of DOCA salt significantly increased the systolic and diastolic blood pressure compared to sham-operated control rats. When treated with chloroform (CFM), ethyl acetate (EAFM) or methanol fractions of M. maderaspatana (MFM), EAFM alone significantly lowered the systolic and diastolic blood pressure. The levels of magnesium and copper significantly increased in plasma and decreased in tissues while the zinc level significantly increased in plasma and tissues, and administration of EAFM brought these parameters back to sham-operated control levels. By GC-MS analysis, phytochemicals such as coumarin, vallinic acid, p-coumaric acid, gallic acid, caffeic acid, and ferulic acid were identified in EAFM. In conclusion, the EAFM controls blood pressure in DOCA-salt hypertensive rats and reverts the metabolic alterations in magnesium, copper and zinc.